Dibenzoazepine and dibenzooxazepine TRPA1 agonists

Abstract

The present invention is related to novel tricyclic compounds of formula (I) having TRPA1 receptor agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use as pharmacological tools, or as irritant incapacitants, or in the treatment of diseases linked to the modulation of the TRPA1 receptors in animals, in particular humans.

The invention claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         or any stereochemically isomeric form thereof wherein 
         A is CH 2 , CO, or O; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from hydrogen, halo, hydroxy, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyloxy, polyhaloC 1-6 alkyloxy, COOR 9  or CONR 10 R 11 ; 
         wherein R 9 , R 10  and R 11  are each independently selected from hydrogen, C 1 - 6 alkyl, C 1-4 alkyloxyC 1-4 alkyl, polyhaloC 1-6 alkyl, polyhaloC 1-4 alkyloxyC 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4 alkyl, aminoC 2-5 alky, mono- or (diC 1-4 alkyl)aminoC 2-5 alkyl; and 
         wherein NR 10 R 11  may form a heterocyclic ring selected from pyrrolidine, piperidine, morpholine, piperazine, or piperazine substituted with C 1-4 alkyl; 
         provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is defined as COOR 9  or CONR 10 R 11 ; and 
         provided that when radical A represents O then the substituents R 5 , R 6 , R 7  and R 8  are not COOR 9 ; 
         or a pharmaceutically acceptable salt thereof, or an N-oxide thereof. 
       
     
     
       2. A compound as claimed in  claim 1  wherein one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is COOR 9 , wherein R 9  is C 1-4 alkyl. 
     
     
       3. A compound as claimed in  claim 1  wherein one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is COOR 9 , wherein R 9  is C 1-4 alkyl, and the other R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  substituents are hydrogen and A is CH 2 , CO or O. 
     
     
       4. A compound as claimed in  claim 1  wherein R 4  is COOR 9  wherein R 9  is C 1-4 alkyl, and the substituents R 1 , R 2 , R 3 , R 5 , R 6 , R 7  and R 8  are hydrogen and A is CH 2  or O, or R 6  is COOR 9  wherein R 9  is C 1-4 alkyl, and the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 7  and R 8  are hydrogen and A is CH 2 , or R 5  is COOR 9  wherein R 9  is C 1-4 alkyl, and the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are hydrogen and A is CH 2 . 
     
     
       5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound of  claim 1 . 
     
     
       6. A process for preparing a pharmaceutical composition, wherein a therapeutically active amount of a compound of  claim 1  is intimately mixed with a pharmaceutically acceptable carrier. 
     
     
       7. A compound of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from hydrogen or CONR 10 R 11 . 
     
     
       8. A compound of  claim 7 , wherein R 10  and R 11  are each hydrogen. 
     
     
       9. A compound of formula (I) 
       
         
           
           
               
               
           
         
         or any stereochemically isomeric form thereof wherein 
         A is CH 2 , or O; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from hydrogen, COOR 9  or CONR 10 R 11 ; 
         wherein R 9 , R 10  and R 11  are each independently selected from hydrogen, C 1-6 alkyl or C 1-4 alkyloxyC 1-4 alkyl; and 
         wherein NR 10 R 11  may form a piperazine, or piperazine subsituted with C 1- 4 alkyl; 
         provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is defined as COOR 9  or CONR 10 R 11 ; and 
         provided that when radical A represents O then the substituents R 5 , R 6 , R 7  and R 8  are not COOR 9 ;
 or a pharmaceutically acceptable salt thereof, or an N-oxide thereof. 
 
       
     
     
       10. A compound of  claim 7 , wherein R 4  is CONR 10 R 11 . 
     
     
       11. A compound selected from the group consisting of;
 methyl 11H-dibenzo[b,e]azepine-8-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-10-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-2-carboxylate; 
 11H-dibenzo[b,e]azepine-10-carboxylic add; 
 N,N-diethyl-11H-dibenzo[b,e]azepine-10-carboxamide; 
 N-(3-methoxypropyl)-11H-dibenzo[b,e]azepine-10-carboxamide; 
 (11H-dibenzo[b,e]azepin-2-yl)(4-methylpiperazin-1-yl)methanone; 
 11H-dibenzo[b,e]azepine-10-carboxamide; 
 methyl dibenzo[b,f][1,4]oxazepine-3-carboxylate; 
 methyl dibenzo[b,f][1,4]oxazepine-4-carboxylate; 
 butyl 11H-dibenzo[b,e]azepine-10-carboxylate; 
 butyl 11H-dibenzo[b,e]azepine-10-carboxylate hydrochloride; 
 (11H-dibenzo[b,e]azepin-9-yl)(4-methylpiperazin-1-yl)methanone; 
 isopropyl 11H-dibenzo[b,e]azepine-8-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-1-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-4-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-7-carboxylate; 
 methyl 11H-dibenzo[b,e]azepine-3-carboxylate; 
 dibenzo[b,f][1,4]oxazepine-4-carboxamide; 
 dibenzo[b,f][1,4]oxazepine-6-carboxamide; 
 methyl 11H-dibenzo[b,e]azepine-1-carboxylate hydrochloride; and 
 methyl 11H-dibenzo[b,e]azepine-4-carboxylate hydrochloride.